Project Summary Malaria remains an enormous problem, and drugs are of critical importance to treat episodes of malaria, prevent disease in high risk groups, and limit transmission. Artemisinin-based combination therapies (ACTs), mostly artemether-lumefantrine or artesunate-amodiaquine, are the cornerstones of antimalarial therapy in Africa. Standard chemoprevention approaches are intermittent preventive therapy with sulfadoxine- pyrimethamine (SP) in pregnant women and seasonal malaria chemoprevention with amodiaquine+SP in children in the Sahel sub-region, and improved approaches are under study. In this context, antimalarial drug resistance is of great concern. Resistance to ACTs, including both artemisinins and partner drugs, has emerged in southeast Asia. Resistance to amodiaquine and SP is longstanding, but sensitivities vary, with uncertain impacts on chemoprevention. Definitive studies in at risk populations of associations between exposure to antimalarial drugs, treatment and preventive efficacy, and selection of drug resistance are needed. This project will build on studies in Uganda during our first cycle of funding in which we characterized the pharmacokinetics (PK) and pharmacodynamics of the ACT dihydroartemisinin-piperaquine, the most promising new agent for chemoprevention in Africa. Our goals will be broadened to gain insights into associations between drug exposure, malaria outcomes, birth outcomes, and selection of drug resistance in the context of the 3 primary indications for antimalarial drugs in Africa: treatment of malaria, chemoprevention in pregnancy, and chemoprevention in children exposed to seasonal malaria. A guiding principal is that the best means of preventing selection of drug resistance is to effectively treat and prevent malaria, as inadequate exposure to antimalarial drugs increases risks for both drug sensitive and drug resistant malaria. Our studies will build on our pharmacology expertise and longstanding collaborations between UCSF and malaria research groups in Uganda and Burkina Faso. We will use rigorous PK assessments to test related hypotheses in children in Uganda and Burkina Faso and pregnant women in Uganda that exposure to ACTs is associated with risks of malaria and the selection of drug-resistant parasites. Better characterization of associations between drug exposure and clinical and drug resistance outcomes will help us to optimize use of drugs for the treatment and prevention of malaria. Specific aims will be: 1) to characterize associations between exposure to key ACT partner drugs, clinical outcomes, and selection of drug resistance in Ugandan children treated for malaria, 2) to evaluate associations between exposure to DP and SP and protection against malaria and adverse birth outcomes in pregnant Ugandan women, and 3) to characterize associations between exposure to seasonal malaria chemoprevention drugs and malaria outcomes in children in Burkina Faso. These studies will help to identify regimens that offer optimal treatment and preventive efficacy against malaria with minimal selection of antimalarial drug resistance.